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@ARTICLE{Grn:307463,
      author       = {S. Grün and A. Rensing-Ehl and T. Suske and J. Wolter-Mess
                      and J. Gehrig and J. Mann and C. König and M. Hauri and M.
                      Heeg and T. R. Leahy and D. Genevieve and J.-B. Gaillard and
                      M. Broly and A. Bourdin and C. Castro and L. Seidel and B.
                      Bengsch and P. Aichele and K. Weißert and J. Fernandez-Orth
                      and V. Schipperges and G. Andrieux and M. Boerries$^*$ and
                      N. Cabezas-Wallscheid and M. Erlacher and R. Elling and C.
                      Speckmann and L. Heller and B. Schulte and M. Lorenz and K.
                      Schwarz and R. Moriggl and S. Ehl},
      title        = {{S}omatic {STAT}5{BN}642{H} mutations shape variable immune
                      landscapes resulting in heterogenous immune diseases.},
      journal      = {The journal of allergy and clinical immunology},
      volume       = {nn},
      issn         = {0091-6749},
      address      = {Amsterdam [u.a.]},
      publisher    = {Elsevier},
      reportid     = {DKFZ-2025-03062},
      pages        = {nn},
      year         = {2025},
      note         = {epub},
      abstract     = {Inborn errors of immunity (IEI) are traditionally
                      understood as monogenic germline disorders. However, somatic
                      mosaicism can also result in immune-mediated diseases,
                      mimicking IEI. While early postzygotic mosaicism is the
                      predominant mechanism, genetic variants causing a selective
                      advantage to hematopoietic progenitors and/or mature immune
                      cells may cause immune dysregulation and initiate disease at
                      any age. Somatic mosaicism for STAT5BN642H was linked to
                      severe allergic disease in infancy but its full clinical
                      spectrum and underlying mechanisms remain incompletely
                      defined.To elucidate how somatic N642H mutations of the
                      STAT5B gene shape lineage-specific mosaicism, immune cell
                      function and clinical phenotypes.We investigated three new
                      patients - including one adult - with STAT5BN642H mosaicism
                      using deep sequencing, flow and mass cytometry, and
                      functional immune assays. Mutant cell distribution was
                      mapped across blood lineages. A mouse model with mosaic
                      STAT5BN642H mutation in hematopoietic stem cells was
                      generated to study clonal dynamics and immune
                      phenotypes.Patients displayed variable lineage mosaicism
                      correlating with two predominant clinical outcomes:
                      early-onset severe atopy with hypereosinophilia, and
                      autoimmune-lymphoproliferative immunodeficiency with
                      expansions of CD8 and γδ T cells. Functional studies
                      revealed enhanced IL-2-mediated proliferation, effector
                      differentiation, and oligoclonal T cell expansions. In mice,
                      a few mutant HSCs reproduced the patient lineage-skewed
                      immune landscapes with variable growth advantage of mutant
                      cells across hematopoietic development and recapitulated
                      patient T cell phenotypes. Targeted mTOR inhibition
                      successfully controlled lymphoproliferation in patients.Our
                      findings illuminate how a single somatic variant in few stem
                      cells can remodel hematopoiesis, generating variable immune
                      mosaics and heterogeneous immune disease.},
      keywords     = {Atopy (Other) / Autoimmunity (Other) / Clonal hematopoiesis
                      (Other) / Hematopoietic stem cells (Other) / Immune
                      dysregulation (Other) / STAT5B (Other) / Somatic mosaicism
                      (Other) / T cell lymphoproliferation (Other) / mTOR
                      inhibition (Other)},
      cin          = {FR01},
      ddc          = {610},
      cid          = {I:(DE-He78)FR01-20160331},
      pnm          = {899 - ohne Topic (POF4-899)},
      pid          = {G:(DE-HGF)POF4-899},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:41453450},
      doi          = {10.1016/j.jaci.2025.12.993},
      url          = {https://inrepo02.dkfz.de/record/307463},
}